Recent studies suggest that a combination of sound therapy (ST) and vagus nerve stimulation (VNS) may reverse maladaptive neuronal plasticity and associated tinnitus. In this pilot study, we examined the effects of ST and tVNS in 15 patients with tinnitus. In addition, the effects of tVNS on auditory cortical activation were examined with magnetoencephalography (MEG) in eight patients with tinnitus. All the patients were examined by standard otologic methods and comprehensive tinnitus tests.The acute effect of tVNS was evaluated by using the WHO well-being index. In the MEG study N1m responses around 100 ms after the onset of probe stimuli were registered in the presence/absence of tVNS. tVNS was delivered at 25 Hz rate to the left tragus. The auditory probe stimulus was presented at tinnitus frequency at comfortable loudness. The tVNS-related artifact was removed with spatiotemporal signal space separation (tSSS) algorithm from the MEG data. Equivalent current dipoles (ECD) where then fitted to the auditory N1m responses. The N1m wave was analyzed in terms of source level amplitude and latency. The ST/tVNS produced increased scores in the WHO wellbeing test, indicating improved mood. The application of tVNS decreased the amplitude of the auditory N1m response. The tVNS effect could be observed in both cortical hemispheres. Auditory cortical activation was modulated by the application of tVNS, suggesting an access to the auditory system through the vagus nerve. Thus, tVNS may have the potential of reducing aberrant activity in the auditory tract that is thought to be associated with tinnitus. The ST/tVNS seems to reduce the distress which often is the major problem in tinnitus patients.

Pathological neural plasticity plays a major role in the genesis and maintenance of chronic tinnitus. Reversal of aberrant plasticity is therefore a promising approach to the treatment of tinnitus. We have developed a novel method to direct highly specific and long lasting neural plasticity. Brief bursts of vagus nerve stimulation (VNS) trigger release of neuromodulators that direct brain changes specific to associated neural activity patterns. Pairing VNS with tones is sufficient to powerfully shape responses in the central auditory system. We have demonstrated that this therapy can be therapeutic in an animal model of tinnitus and in human patients. We are now optimizing the clinical parameters through parallel studies in humans and preclinical studies in animals. VNS-directed plasticity is sensitive to the current used to activate the vagus nerve, to the interval between VNS-tone pairings, and to the behavioral state of the individual during therapy. We will present evidence suggesting that with further study VNS-directed plasticity may be optimized to become a reliable, safe, and long-lasting therapy for chronic tinnitus. Pathological neural plasticity plays a major role in the genesis and maintenance of chronic tinnitus. Reversal of aberrant plasticity is therefore a promising approach to the treatment of tinnitus. We have developed a novel method to direct highly specific and long lasting neural plasticity. Brief bursts of vagus nerve stimulation (VNS) trigger release of neuromodulators that direct brain changes specific to associated neural activity patterns. Pairing VNS with tones is sufficient to powerfully shape responses in the central auditory system. We have demonstrated that this therapy can be therapeutic in an animal model of tinnitus and in human patients. We are now optimizing the clinical parameters through parallel studies in humans and preclinical studies in animals. VNS-directed plasticity is sensitive to the current used to activate the vagus nerve, to the interval between VNS-tone pairings, and to the behavioral state of the individual during therapy. We will present evidence suggesting that with further study VNS-directed plasticity may be optimized to become a reliable, safe, and long-lasting therapy for chronic tinnitus.

3. Paired vagus nerve stimulation for tinnitus - Pilot study results

Vanneste, S., Kilgard, M.P., Engineer, N., Tarver, B., De Ridder D.

Vagus nerve stimulation (VNS) paired with tones has shown efficacy in animal studies. This first-in-human pilot study was undertaken to further explore paired VNS for tinnitus. Twelve patients consented; 10 met inclusion criteria and were implanted with a helical electrode wrapped around the left cervical vagus nerve with the lead connector end exiting at an abdominal incision. After implant and recovery, patients returned daily for connection to an external stimulator and therapy sessions (½ second VNS paired with tones every 30 seconds for 2.5 hours) for four weeks. Tones were provided through headphones connected to a laptop running proprietary software. Implanted patients averaged 45.4 years of age (23.7 to 59.5), had tinnitus for 5.6 years (1.2 to 14.0 years), and had tried numerous previous therapies including various medications, trans-magnetic stimulation (TMS) and cortical stimulation (tDCS). Eight patients were male; two were female. All patients had tonal tinnitus. In general, stimulation was well-tolerated; adverse events were as expected based on other VNS applications. Each Friday patients completed questionnaires and had audiometric testing. Tinnitus Handicap Inventory response was defined as a 30% decrease in score; Iowa Tinnitus Handicap Questionnaire response was defined as a 10-point decrease; MML response was defined as a 10 dB decrease. At four weeks THI response was 40%; THQ response was 70%; MML response was 60%. Findings from this pilot study suggest that VNS paired with tones could become an effective therapy for the treatment of tinnitus. Development of a fully implantable device has commenced.

4. Virtual reality exposure therapy for unilateral tinnitus

Viaud-Delmon I., Londero A., Bonfils P., Warusfel O.

We have developed dedicated auditory and visual 3D virtual reality environments in which tinnitus sufferers are given the possibility to voluntarily manipulate an auditory and visual image of their tinnitus. This study examined the data of all participants that were undergoing virtual reality treatment as part of a randomized clinical trial comparing virtual reality therapy and cognitive behavior therapy to a wait list control for the treatment of unilateral tinnitus. The current study utilized data from all individuals who were treated with virtual reality exposure therapy. After a first session devoted to the creation of an acoustic replica of the patient’s tinnitus that is further included into the virtual environments, 50 patients have followed 8 sessions of virtual reality. During each session, the patients had a trajectory to follow in a virtual environment in which they had to manipulate an auditory and visual representation of their tinnitus. Presence, cybersickness and state anxiety levels were assessed at each session. Results of virtual reality treatment on behavioral measures at post-treatment suggest that they generalize to the real world. Cybersickness, anxiety and presence during immersion are important factors for treatment outcome. Dismantling research methodology is needed to separate the contribution of the various components at stake in this virtual reality treatment. Understanding the processes would help implementing virtual reality into clinical practice given that treatment outcome would be better predictable.

To define the effect of Hyperbaric Oxygen Treatment (HBOT) on post traumatic central-type chronic disabling tinnitus.The study was aimed to include patients suffering from post traumatic chronic disabling tinnitus of the central type. Patients were included if they were 1-5 years post the traumatic events. Tinnitus was typed using Tinnitus disabling score questionnaire, a full oto-neurological physical examination, a complete hearing evaluation (including audiometry up to 20,000 Hz, and ABR). A complete Tinnitus matching score and brain SPECT scan for perfusion were performed. The study was a cross-over, randomized trial and patients were randomly assigned to receive HBOT after their first or second evaluation (2 months later). The evaluations were performed at baseline and 2 months after for all. The control group had a third repeated evaluation after the cross mach (≈4 months from baseline), when they have completed the HBOT. The HBOT included 40 sessions of 60 minutes exposure to 100% oxygen at 1.5 Atmosphere pressure, 5 days per week. Except for the tinnitus, dizziness, neuro-cognitive status, quality of life, and brain SPECT scan were also assessed at each of the evaluation points. Twenty one patients had completed the study protocol. No significant improvement was notice in the control group during the control period. Seven of the patients suffered from prior whiplash injury, 11 from blunt head injury and one from direct blunt injury to the ear. Fourteen out of 21 patients (66%) reported a major improvement of their tinnitus after the HBOT. Six of these patients (21%) reported that the tinnitus ceased completely. All of the patients (100%) reported a significant improvement in their quality of life. Thirteen out of the 18 patients (72%) who also complained of post traumatic dizziness, reported a significant improvement following the treatment. A major cognitive function improvement (NeuroTrax, Mindsteam) was found in 15 out of 19 (79%). An objective brain SPECT scan improvement in brain perfusion was demonstrated in correlation to the improvement in tinnitus. In patients with chronic post traumatic disabling tinnitus of the central type, HBOT was found to be a useful treatment with about 66%. This is the first study that the demonstrate the favorable effect of HBOT for these patients and further studies are needed in order to defined the optimal sub-group of patient that will benefit the most.

Repetitive transcranial magnetic stimulation (rTMS) is regarded as a potential treatment modality for chronic tinnitus. Although previous studies demonstrated a slight therapeutic effect, optimal rTMS parameters and tolerability of multisession protocols remain to be specified. By combining various protocols, the objective of our study was to assess and characterize the effectiveness of conventional rTMS in patients with chronic severe tinnitus, while controlling safety and tolerability. A randomized, double-blind, sham-controlled procedure, with four increasing levels of magnetic “pseudo-dose” was designed. Each level comprised 16 patients randomly assigned to active rTMS group (12 patients) or sham rTMS group (4 patients). The neuronavigated rTMS was centered over the primary auditory cortex contralateral to the perceived predominant side of tinnitus. Effectiveness on tinnitus loudness, severity and handicap was assessed through visual analog rating scale, multidimensional self-questionnaires and tinnitometry. Safety and tolerance for rTMS sessions were evaluated through a semi-structured interview for adverse events and tonal audiometry for hearing status. The follow-up was spread over six months. Using a mixed-effects model for comparison to baseline measures, we showed that sham rTMS was more effective on tinnitus perception than active rTMS, regardless of the protocol. This paradoxical effect could be related to the higher incidence of specific magnetic stimulation related side effects (headache, facial contractions and pain) in groups with active rTMS. Our findings question the therapeutic benefit of rTMS in tinnitus. Major multicenter clinical trials remain to be done. The simultaneous exploration of the various rTMS parameters, as well as taking into account the potentially negative side effects of rTMS, could enhance the methodological validity of these studies and help identify the optimal therapeutic protocol.